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In this video, Jeremy Faust, MD, editor-in-chief of 番茄社区, and Robert Califf, MD, commissioner of the FDA, discuss the limitations of the FDA in drug production and sales, controversial decisions, and where politics come into play. Part One of this conversation focused on what the end of the U.S. public health emergency will mean for COVID care.

The following is a transcript of their remarks:

Faust: The FDA made really big news last week about moving Narcan, nasal naloxone, over-the-counter. This is an opioid-reversal antidote, it saves lives when given in time, and I thought that was a great move. I think it's got a lot of support.

One of my readers had a question about what the FDA can do to make sure that price-gouging doesn't happen, and the example cited was EpiPens. When one company bought the device from a competitor, the price went up from $94 to $700. Are you worried about Narcan, or nasal naloxone, following the same pathway? What can the FDA do to make sure that what you're trying to achieve actually occurs, which is to get this drug to those who need it?

Califf: We have limits, as you know, when it comes to [this]. We can't set the price of a drug. We can't tell a manufacturer to make a drug and enforce it. We can encourage them to give a reasonable price and to make enough.

This is not the same as the EpiPen situation in any way. I'll just give you a couple reasons why. Number one, we have spent a lot of time with CMS on this issue, because when something goes over-the-counter, then CMS can't pay for it by law. But, there are mechanisms that we're going to use to try to make sure that the drug is available either free or at a reasonable price, depending on the circumstance.

Importantly, this is just one form of naloxone. There are many others that will still be on the market by prescription. And a little-known fact that I learned a lot about over the last few months is that the majority of naloxone is now actually distributed by public health groups who buy it in bulk and then distribute it essentially for free.

As a cardiologist, this analogy is easy for me: we don't charge people for defibrillators. If you dropped over dead in your office and got an external defibrillator shock, you wouldn't be charged ahead of time for that. I think naloxone is a very similar thing. It can save a life, so we have to make it available.

We'll get it worked out. But I don't want anyone to think that the FDA can actually set the price or enforce that a manufacturer makes a drug. We don't have that legal authority.

Faust: I want to move to a different topic, just generally speaking about some controversial approvals and pathways related to that.

The FDA's accelerated approval pathway has definitely had its moments, and I think the Alzheimer's drug issue is kind of the sine qua non example of that. Is FDA changing its approach to the accelerated approval pathway based on that example and others?

Califf: You know, it's always interesting that out of all the accelerated approvals, this one gets the attention. It's an important disease and a difficult issue.

The basic answer is, we're not changing our general approach. I mean, the American public has spoken through Congress and the laws to create the accelerated approval pathway. It's clearly laid out for when there is a disease without an adequate treatment -- that's a serious disease, life-threatening or very serious -- and it's based on the opinion of the FDA full-time civil servants -- not political appointees like me, but the people in the centers who don't have a financial conflict of interest -- that a biomarker that's measured is reasonably likely to predict a clinical benefit.

Now, what has changed with our support is a change in the law with the omnibus bill that just passed, that gives us much more authority to require, for example, that companies start their confirmatory trial before the accelerated approval and better authority that if things don't work out in the confirmatory trial, that the drug can be pulled from the market.

So things are being tuned-up with accelerated approval, but the American public, compared to many other societies, is willing to take greater risk for potential greater benefit. That's manifested through laws that the elected officials have passed.

I think a good way to think about the FDA is we're more like referees than anything else. We have a rule book -- that's the laws that are passed by Congress. We do interpret the rules, and that's a really important part of our jobs. But fundamentally, we're not the teams that are playing on the playing field, we're the referees.

Faust: With respect to that, though, you have to figure out which fouls to call. That's part of the job of a ref, to let 'em play or to enforce.

You do set certain standards -- you talked about biomarkers being a reasonable proxy, that being enough, especially for certain diseases. But how do you feel about FDA approving a drug that missed its own primary goal? Like, this study is done by industry and it missed their own primary outcomes. In these studies, can an approval of a substance like that really be justified based on secondary outcomes or if we see a signal there? What do you think? Where do you weigh in on that?

Califf: Of course, it's interesting to do the Monday morning quarterbacking after the game is over, was the call right? My job as commissioner is not to make the calls, those are made by the full-time civil servants based on their best judgment.

Is it 100% of the time wrong when a primary endpoint is not met in one trial to say that all the other evidence is thereby invalidated? I don't think anything is 100%. That's why we have people making these judgments.

I disagree with some of the judgments made by FDA people during the course of my work, but the fact is that this is what they do for a living. They cannot have a conflict of interest in their work, and no referee gets it right 100% of the time. In this case, on Alzheimer's, the story's not over yet, right? Maybe we should have this conversation in a year.

One other point to keep in mind about FDA, because the information that FDA sees that's not from a particular drug or device is confidential, that other companies may be in development, FDA gets to see a lot of data in the field that are not publicly available. We'll see when the whole story is done on this, but just keep in mind that the drama of the public proceeding is only a part of this entire story of how drugs get evaluated and approved.

There's nothing wrong with criticizing, that's part of our job, is to listen to criticism and get better.

Faust: We'll be watching that story.

You mentioned something about how you've got at the FDA the professionals and the advisory committees, and then there's you, the commissioner of the FDA. Do you have in your role the ability and wherewithal and desire to override those pieces of advice? Be it an advisory committee or a policy?

Califf: First of all, let's be clear, advisory committees are advisory. They are not decision making. In fact, as we're re-evaluating advisory committees, we want to have more advisory committees but less voting, because people get all worked up about the voting and the voting doesn't matter. What the FDA wants to know is, what is the thinking behind the reasons someone might vote one way or another? We need knowledge that we may not have inside the FDA.

When it comes to the commissioner, there is a chain of command. There's literally a chain of command by law that goes all the way to the president.

Everyone above the center directors at the FDA are political appointees, and I'm on record in 2016 in the case of Sarepta as adhering to what's been the standard for all FDA commissioners, which is that you would only overrule the judgment of the civil service in an extreme situation. For example, corruption was detected or someone was temporarily insane and made a bad decision at the center director level.

Once you open the floodgate of political appointees making decisions about drug approvals or device approvals, where would it stop? I'd urge you to think about some of the politicians that have been elected in America. Would you want them reaching in with the connections to companies that they have and overruling the decision of full-time civil servants?

I think it's much better, like refereeing in sports, to live with the decisions of referees. I'm a Duke guy, that call at the end of the Virginia game was one of the worst calls I've ever seen, but you live with it and go on. If consistent bad decisions are made, then you need to look at the personnel and make a change. But if you open this up to politicians, let me tell you, that would be a mess.

So yes, I have the authority. I would use it in extreme circumstances, but it would take something really, really extreme for me to do that.

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